CN118290332A

CN118290332A - Preparation method of polyphenol compound

Info

Publication number: CN118290332A
Application number: CN202410392995.4A
Authority: CN
Inventors: 陈誉; 童亮
Original assignee: Jiangxi University of Science and Technology
Current assignee: Jiangxi University of Science and Technology
Filing date: 2024-04-02
Publication date: 2024-07-05

Abstract

The invention belongs to the technical field of compound synthesis and preparation, and provides a preparation method of a polyphenol compound. The method takes a compound A as a raw material, firstly carries out benzyloxy substitution to protect hydroxyl, then carries out acyl chlorination, acetyl phenyl substitution and cyclization reaction in sequence to obtain an intermediate product M3, and finally removes benzyloxy through hydroxyl halogenation and catalytic hydrogen substitution to obtain a target product polyphenol compound B. The invention provides a new synthetic route of polyphenol compounds, which has the advantages of green and safe raw materials, simple reaction conditions, high yield and high purity of target products, and can be used for large-scale production.

Description

Preparation method of polyphenol compound

Technical Field

The invention belongs to the technical field of compound synthesis and preparation, and relates to a preparation method of a polyphenol compound.

Background

Neurodegenerative disorders such as diabetes, parkinson's disease, huntington's chorea, alzheimer's disease, non-Alzheimer's dementia, multiple sclerosis, traumatic brain injury, spinal cord injury or ALS, etc., have a great influence on the quality of life of the patient. Existing treatment methods have certain limitations, and there is an urgent need to find novel drugs with multiple neuroprotective properties.

Chinese patent application CN103929959a discloses a neuroprotective polyphenol analogue (shown as formula i), a synthetic analogue of certain polyphenols such as feissones, baicalein or chlorogenic acid, having neuroprotective, anti-inflammatory, glutathione-promoting and/or antioxidant properties, useful for promoting, enhancing and/or increasing the protection, growth and/or regeneration of neurons.

The polyphenol compound can be obtained by extracting and separating natural plants containing the polyphenol compound as raw materials, but the extraction process has higher requirements on experimental conditions and instruments, lower yield, multiple types of extracts and complex post-separation treatment. The chemical synthesis can obtain the target compound through reasonable synthesis route design, has the characteristics of simple process, high yield and less byproducts, and is to be researched in the preparation of the neuroprotective polyphenol compound.

The Chinese patent application CN109020940A discloses a method for synthesizing scutellarin, which comprises the following steps: step 1) synthesizing ethyl p-methoxybenzoyl acetate by adopting ethyl acetoacetate and p-methoxybenzoyl chloride as raw materials; step 2) synthesizing p-methoxybenzoyl ethyl acetate and 3,4, 5-trimethoxyphenol to obtain 5,6,7,4' -tetramethoxy flavone; step 3) removing methyl from 5,6,7,4' -tetramethoxyflavone to obtain crude scutellarin, and purifying the crude scutellarin to obtain high-content refined scutellarin (shown in formula II). Although the method solves the problems of low yield and dangerous reagent use in the prior art, the reaction process requires high pressure conditions and the reaction conditions are harsh.

Chinese patent CN104926768B discloses a synthesis method of threo limonin, iso-wogonin and norwogonin, comprising the following steps, (1) reacting 5, 7-dimethoxy-8-bromo-flavone with sodium methoxide under the catalysis of cuprous salt to generate 5,7, 8-trimethoxyflavone; (2) Under the action of aluminum trichloride, 5,7, 8-trimethoxy flavone reacts in inert atmosphere to obtain the threo-limonin. On the basis of the method, su Jizhu Huang Tongtuo methyl groups can be further processed to respectively obtain the iso-wogonin and the norwogonin (the structure is shown as a formula III). The method has the advantages of wide raw material sources, good selectivity and mild conditions, but the yield is still lower, and the maximum is only 60%.

PAMELA MAHER ET AL in "Chemical Modification of the Multitarget Neuroprotective Compound Fisetin"(J.Med.Chem.2012,55,378-389), discloses the synthesis of quinoline derivatives (see formula IV) by condensing 2' -amino-paracetamol with an appropriately substituted aldehyde using sulfuric acid in methanol with a final yield of 15-40%.

In general, the existing synthesis methods mainly have the problems of environmental pollution of raw materials, harsh reaction conditions, and particularly low yield of target products, thereby limiting the wide application of the compounds.

Disclosure of Invention

Aiming at the problems existing in the prior art, the invention provides a preparation method of a polyphenol compound, which takes a compound A as a raw material, firstly carries out benzyl substitution to protect hydroxyl, then carries out acyl chlorination, acetyl phenyl substitution and cyclization reaction in sequence to obtain an intermediate product M3, and finally carries out hydroxyl halogenation and catalytic hydrogen substitution to obtain a target product polyphenol compound B. The route has the advantages of green and safe raw materials, simple reaction conditions, ideal target product yield and high purity, and can be used for large-scale production.

The invention provides a preparation method of polyphenol compounds, the synthetic route is as follows:

Wherein R ₁ represents 2-3-OH groups, R ₂ represents the same-OCH ₂ Ph groups as the-OH substitution positions and the same number in R ₁;

the method specifically comprises the following steps:

Step I: adding a raw material compound A, benzyl bromide and inorganic base into an organic solvent A, heating for reaction, cooling to room temperature after the reaction is finished, filtering, adding alkali metal hydroxide, stirring for reaction, and obtaining an intermediate product M1;

Step II: taking an intermediate product M1 for acyl chlorination reaction, removing a solvent after the acyl chlorination reaction is finished, and dissolving the solvent in dichloromethane to obtain a reaction liquid 1; dissolving 2-aminoacetophenone in an organic solvent B, and adding triethylamine to obtain a reaction solution 2; dropwise adding the reaction liquid 2 into the reaction liquid 1, and stirring for reaction to obtain an intermediate product M2;

step III: mixing an intermediate product M2, 1, 4-dioxane and alkali metal hydroxide, and heating to react to obtain an intermediate product M3;

Step IV: adding an intermediate product M3, bromocyclopentane and inorganic base into an organic solvent C, and stirring for reaction to obtain an intermediate product M4;

step V: and adding the intermediate product M4 and the palladium-carbon catalyst into the organic solvent D, and introducing hydrogen for replacement to obtain the polyphenol compound.

Further, the compound A is selected from 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid, 3, 5-dihydroxybenzoic acid, 3,4, 5-trihydroxybenzoic acid or 2,4, 6-trihydroxybenzoic acid; the benzyl halide is selected from benzyl chloride or benzyl bromide.

Further, in step I and step IV, the inorganic base is independently selected from potassium carbonate, sodium carbonate and/or sodium hydride; in step I and step III, the alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide and/or lithium hydroxide.

Further, in the step II, the acyl chlorination reaction process is as follows: firstly, adding dichloromethane into the intermediate product M1, then adding N, N-dimethylformamide or N-methyl-N-phenylformamide, and dripping an acyl chloride reagent for reaction.

Still further, the intermediate M1, the acid chlorinating agent, methylene chloride and N, N-dimethylformamide or N-methyl-N-phenylformamide were used in a ratio of 1g:0.5-50mol:1-100mL:0.5-50mL.

In some embodiments of the invention, the acid chloride reagent is selected from oxalyl chloride, thionyl chloride, or phosphorus oxychloride.

Further, the acid chlorination reaction is carried out at 20 to 30 ℃.

Further, the organic solvent a is selected from N, N-dimethylformamide or N-methyl-N-phenylformamide; the organic solvent B is selected from acetonitrile, dichloromethane, ethylene glycol dimethyl ether, methanol or acetone; the organic solvent C is selected from N, N-dimethylformamide or N-methyl-N-phenylformamide; the organic solvent D is at least one selected from acetonitrile, dichloromethane, ethylene glycol dimethyl ether and methanol.

Further, in the step I, the dosage ratio of the compound A, benzyl bromide and inorganic base is 1mol:0.35-35mol:0.5-50mol; the molar ratio of the compound A to the alkali metal hydroxide is 1:0.2-20.

Further, in the step II, the dosage mole ratio of the intermediate product M1, triethylamine and 2-aminoacetophenone is 1mol:0.5-50mol:0.105-10.5mol.

Further, in the step III, the ratio of the amount of the intermediate M2, 1, 4-dioxane and the alkali metal hydroxide is 1mol:1-100mL:0.25-25mol.

Further, in the step IV, the dosage ratio of the intermediate product M3, the bromocyclopentane and the inorganic base is 1mol:0.1-10mol:0.2-20mol.

Further, in the step V, the mass ratio of Pd to C in the palladium-carbon catalyst is 0.03-0.3:1, a step of; the palladium carbon catalyst is used in an amount of 8 to 12wt% of the intermediate product M4.

Preferably, in the step v, the mass ratio of Pd to C in the palladium-carbon catalyst is 0.1:1, a step of; the palladium on carbon catalyst was used in an amount of 10wt% of the intermediate product M4.

Further, in the step I, the heating reaction temperature is 0-80 ℃.

Further, in the step II, the stirring reaction is carried out at 0-20 ℃.

Further, in the step III, the temperature is 50-100 ℃.

Further, in the step IV, the stirring reaction temperature is 50-100 ℃.

Compared with the prior art, the invention has the following beneficial effects:

(1) The invention takes polyhydroxy compound as raw material, protects hydroxyl by benzyloxy substitution, and finally obtains polyphenol compound by catalytic hydrogen replacement after series reaction; compared with the traditional preparation process, the preparation method has the advantages of green and pollution-free;

(2) The synthetic route of the invention does not relate to the reaction process with harsh conditions, has simple operation and high efficiency, can realize purification treatment by recrystallization, and does not need operations such as column chromatography and the like; meanwhile, the yield of each reaction step reaches more than 90% on the premise of ensuring the purity of the product by optimizing the dosage proportion of reactants and the reaction temperature in each reaction process, so that the yield of the overall reaction is improved;

(3) The method has simple integral route and easy operation, and is suitable for industrialized amplified production.

Drawings

FIG. 1 is a synthetic route diagram of the polyphenol compound of the present invention;

FIG. 2 is a nuclear magnetic H-profile of intermediate M3 (N- (2-acetylphenyl) -3, 4-bis (benzyloxy) benzamide) prepared according to example 3 of the invention;

FIG. 3 is a nuclear magnetic H-pattern of intermediate M4 (2- [3, 4-bis (benzyloxy) phenyl ] quinolin-4-ol) prepared according to example 4 of the invention;

FIG. 4 is a nuclear magnetic resonance H-spectrum of a target product compound B (4- (4- (cyclopentyloxy) quinolin-2-yl) benzene-1, 2-diol) prepared in example 5 of the present invention.

Detailed Description

The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the invention as claimed.

The synthetic route of the polyphenol compound of the present invention is shown in FIG. 1.

The preparation method of the present invention will be described in detail by taking the synthesis of polyphenol compound 4- (4- (cyclopentyloxy) quinolin-2-yl) benzene-1, 2-diol as an example.

Example 1

The intermediate M1 (3, 4-bis (benzyloxy) benzoic acid) was prepared as follows:

(1) 25g (0.162 mol) of raw material 3, 4-dihydroxybenzoic acid is taken and added into 250mL of N, N-dimethylformamide, 112g (0.81 mol) of potassium carbonate and 97g (0.567 mol) of benzyl bromide are added, the temperature is raised to 40 ℃, the mixture is stirred for 2 hours, and the reaction is stopped after the thin layer chromatography monitors that the raw material is reacted;

(2) Cooling the reaction solution to room temperature, filtering to remove potassium carbonate, adding 13g (0.324 mol) of sodium hydroxide into the mother solution, stirring for 1h at room temperature, monitoring the reaction completely by using thin layer chromatography, and stopping the reaction;

(3) Adding 3mol/L hydrochloric acid into the reaction solution to adjust the pH to 5.0, pouring the reaction solution into 1250mL of water, stirring, precipitating a white solid, filtering, drying, dissolving the white solid by using 250mL of methanol under heating, crystallizing at room temperature, filtering, and drying to obtain 51.33g of white solid intermediate product M1, wherein the yield is 95.15% and the purity is 95.11%.

Comparative examples 1 to 1

The other steps are consistent, (2) the reaction solution is cooled to room temperature, the potassium carbonate is removed by filtration, 13g (0.324 mol) of sodium hydroxide is added into the mother solution, the mixture is stirred for 2 hours at room temperature, the reaction is monitored to be complete by thin layer chromatography, and the reaction is stopped; m1 yield 80.05% and purity 95.24%.

Comparative examples 1 to 2

Other steps are consistent, (3) 3mol/L hydrochloric acid is added into the reaction liquid to adjust the pH value to 4.5, the reaction liquid is poured into 1250mL of water, stirred, white solid is separated out, filtered, dried, the white solid is heated and dissolved by 250mL of methanol, crystallized at room temperature, filtered and dried, 38.35g of white solid intermediate product M1 is obtained, and the yield is 71.02% and the purity is 95.40%.

Example 2

The intermediate M2 (N- (2-acetylphenyl) -3, 4-bis (benzyloxy) benzamide) was prepared as follows:

(1) Taking 20g (0.06 mol) of intermediate product M1, adding into 200mL of dichloromethane, adding 0.5mL of N, N-dimethylformamide, dropwise adding 0.3mol of oxalyl chloride at 0 ℃, monitoring the reaction of the raw materials by using a thin layer chromatography, concentrating and drying, and adding 200mL of dichloromethane to obtain a reaction solution 1;

(2) Taking 8.52g (0.063 mol) of 2-aminoacetophenone, adding 200mL of dichloromethane for dissolution, and adding 0.315mol of triethylamine to obtain a reaction liquid 2;

(3) Dropwise adding the reaction liquid 2 into the reaction liquid 1, stirring at room temperature after the dropwise adding, and stopping the reaction after the reaction of the raw materials is monitored by a thin layer chromatography;

(4) And (3) adding 200mL of water into the reaction solution in the step (2), washing the reaction solution, sequentially washing the reaction solution with saturated sodium bicarbonate solution and saturated saline water, drying the reaction solution by anhydrous sodium sulfate, concentrating the reaction solution to dryness, adding 200mL of methanol for heating and dissolving, cooling and crystallizing, filtering and drying the reaction solution to obtain 24.96g of white solid intermediate product M2, wherein the yield is 95.21% and the purity is 93.11%.

Example 2-1

Taking 20g of intermediate product M1, adding the intermediate product M1 into 200mL of dichloromethane, adding 0.5mL of N, N-dimethylformamide, dropwise adding 0.3mol of oxalyl chloride at 5 ℃, monitoring the reaction of the raw materials by using a thin layer chromatography, concentrating and drying, and adding 200mL of dichloromethane to obtain a reaction solution 1; the yield of M2 is 93.97% and the purity is 94.52%.

Comparative example 2-1

Taking 20g of intermediate product M1, adding the intermediate product M1 into 200mL of dichloromethane, adding 0.5mL of N, N-dimethylformamide, dropwise adding 0.3mol of oxalyl chloride at 40 ℃, monitoring the reaction of the raw materials by using a thin layer chromatography, concentrating and drying, and adding 200mL of dichloromethane to obtain a reaction solution 1; the yield of M2 is 84.15% and the purity is 93.03%.

Example 3

The intermediate M3 (2- [3, 4-bis (benzyloxy) phenyl ] quinolin-4-ol) was prepared as follows:

(1) 30g (0.066 mol) of intermediate M2 is taken, 58.15g (0.66 mol) of 1, 4-dioxane and 6.6g (0.165 mol) of sodium hydroxide are added, the temperature is raised to 90 ℃, the reaction is monitored by thin layer chromatography, and the reaction is stopped;

(2) To the reaction solution of step (1) was added 300mL of water, followed by 300mL of ethyl acetate, extraction, separation of the organic phase, drying, and concentration to obtain 26.94g of intermediate M3 as a white solid in a yield of 94.26% and a purity of 94.33% (¹ H NMR results are shown in FIG. 2).

Example 3-1

Other steps are consistent, (1) 30g (0.066 mol) of intermediate product M2 is taken, 58.15g (0.66 mol) of 1, 4-dioxane and 6.6g (0.165 mol) of sodium hydroxide are added, the temperature is raised to 80 ℃, and after monitoring the reaction by thin layer chromatography, the reaction is stopped; m3 yield 93.11% and purity 92.21%.

Comparative example 3-1

Other steps are consistent, (1) 30g (0.066 mol) of intermediate product M2 is taken, 58.15g (0.66 mol) of 1, 4-dioxane and 6.6g (0.165 mol) of sodium hydroxide are added, the temperature is raised to 120 ℃, and after monitoring the reaction by thin layer chromatography, the reaction is stopped; m3 yield 89.73% and purity 94.15%.

Comparative example 3-2

Other steps are consistent, (1) 30g (0.066 mol) of intermediate product M2 is taken, 58.15g (0.66 mol) of 1, 4-dioxane and 6.6g (0.165 mol) of sodium hydroxide are added, the temperature is raised to 40 ℃, and after monitoring the reaction by thin layer chromatography, the reaction is stopped; m3 yield 83.86% and purity 92.25%.

Example 4

The intermediate M4 (2- [3, 4-bis (benzyloxy) phenyl ] -4- (cyclopentyloxy) quinoline) was prepared as follows:

(1) 30g (0.07 mol) of intermediate M3 is taken, 300mLN, N-dimethylformamide and 19.35g (0.14 mol) of potassium carbonate are added, the temperature is raised to 80 ℃, the reaction is stirred and stopped after the reaction of the raw materials is monitored by thin layer chromatography;

(2) The reaction solution obtained in the step (1) was added to 400mL of water, and a white solid was precipitated, filtered and dried to obtain 32.42g of a white solid intermediate M4, yield 92.83% and purity 92.43% (¹ H NMR result is shown in FIG. 3).

Comparative example 4-1

The only difference from example 4 is that: the potassium carbonate is replaced with an equimolar amount of silver nitrate. The yield was 60.23% and the purity was 92.12%.

Comparative example 4-2

The only difference from example 4 is that: 0.14mol of potassium carbonate was replaced with 0.1mol of potassium carbonate and 0.04mol of tetrabutylammonium bromide. The yield was 82.51% and the purity was 92.87%.

Comparative examples 4 to 3

The only difference from example 4 is that: step (1) is heated to 40 ℃, the yield is 89.26 percent, and the purity is 92.23 percent

Comparative examples 4 to 4

The only difference from example 4 is that: step (1) is heated to 120 ℃, the yield is 82.55 percent, and the purity is 91.97 percent

Example 5

The preparation of the target compound (4- (4- (cyclopentyloxy) quinolin-2-yl) benzene-1, 2-diol) is carried out as follows:

(1) Taking 24g (0.048 mol) of intermediate product M4, adding dichloromethane/methanol (240 mL/48 mL), adding palladium-carbon catalyst (the dosage is 10wt% of intermediate product M4), introducing hydrogen, stirring at normal temperature and normal pressure for replacement, monitoring the reaction completion by thin layer chromatography, and stopping the reaction;

(2) The reaction liquid in the step (1) is filtered and concentrated to obtain a white solid, 240mL of methanol is added, the mixture is heated and dissolved, the temperature is reduced for crystallization, the mixture is filtered and dried, and 15.05g of a white solid target product is obtained, the yield is 97.66%, and the purity is 90.78% (¹ H NMR results are shown in figure 4).

Comparative example 5-1

The only difference from example 5 is that the palladium on carbon catalyst was used in an amount of 15% by weight of intermediate M4 in a yield of 87.07% and in a purity of 90.12%.

Comparative example 5-2

The only difference from example 5 is that a palladium on carbon catalyst was used in an amount of 5% by weight of intermediate M4, yield 86.51% and purity 89.36%.

The overall yield of 4- (4- (cyclopentyloxy) quinolin-2-yl) benzene-1, 2-diol prepared by this synthetic route was 77.41%.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A preparation method of polyphenol compound is characterized in that the synthetic route is as follows:

the method specifically comprises the following steps:

2. The preparation method according to claim 1, wherein the compound a is selected from 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid, 3, 5-dihydroxybenzoic acid, 3,4, 5-trihydroxybenzoic acid or 2,4, 6-trihydroxybenzoic acid.

3. The process according to claim 1, wherein in step i and step iv, the inorganic base is independently selected from potassium carbonate, sodium carbonate and/or sodium hydride; in step I and step III, the alkali metal hydroxide is independently selected from sodium hydroxide, potassium hydroxide and/or lithium hydroxide.

4. The process according to claim 1, wherein in step ii, the acid chlorination reaction proceeds as follows: firstly, adding dichloromethane into the intermediate product M1, then adding N, N-dimethylformamide or N-methyl-N-phenylformamide, and dripping an acyl chloride reagent for reaction.

5. The process according to claim 4, wherein the ratio of the intermediate M1, the acid chloride, the methylene chloride and the N, N-dimethylformamide or N-methyl-N-phenylformamide is 1g:0.5-50mol:1-100mL:0.5-50mL.

6. The process according to claim 4, wherein the acid chloride reaction is carried out at 20 to 30 ℃.

7. The preparation method according to claim 1, wherein the organic solvent a is selected from N, N-dimethylformamide or N-methyl-N-phenylformamide; the organic solvent B is selected from acetonitrile, dichloromethane, ethylene glycol dimethyl ether, methanol or acetone; the organic solvent C is selected from N, N-dimethylformamide or N-methyl-N-phenylformamide; the organic solvent D is at least one selected from acetonitrile, dichloromethane, ethylene glycol dimethyl ether and methanol.

8. The preparation method according to claim 1, wherein in the step I, the dosage ratio of the compound A, benzyl bromide and inorganic base is 1mol:0.35-35mol:0.5-50mol; the molar ratio of the compound A to the alkali metal hydroxide is 1:0.2-20; in the step II, the dosage mole ratio of the intermediate product M1, triethylamine and 2-amino acetophenone is 1mol:0.5-50mol:0.105-10.5mol; in step III, the ratio of the amount of the intermediate M2, 1, 4-dioxane and the alkali metal hydroxide is 1mol:1-100mL:0.25-25mol; in the step IV, the dosage ratio of the intermediate product M3, the bromocyclopentane to the inorganic base is 1mol:0.1-10mol:0.2-20mol.

9. The preparation method according to claim 1, wherein in the step v, the mass ratio of Pd to C in the palladium-carbon catalyst is 0.03 to 0.3:1, a step of; the dosage of the palladium-carbon catalyst is 8-12wt% of the intermediate product M4; preferably, the mass ratio of Pd to C in the palladium-carbon catalyst is 0.1:1, a step of; the palladium on carbon catalyst was used in an amount of 10wt% of the intermediate product M4.

10. The method of claim 1, wherein in step i, the heating reaction temperature is 0-80 ℃; in the step II, the stirring reaction is carried out at 0-20 ℃; in the step III, the temperature is 50-100 ℃; in the step IV, the stirring reaction temperature is 50-100 ℃.